A clear understanding of the central control of cardiovascular function is a prerequisite for unraveling the mechanisms involved in many cardiovascular diseases. There is a general consensus that L-glutamate is the main excitatory neurotransmitter in different medullary neuronal projections mediating cardiovascular functions. However, the presence of many other putative neurotransmitters and neuromodulators in these neuronal pools has been demonstrated. Three novel endogenous opioid peptides (endomorphin-1, , endomorphin-2, and nociceptin) have recently been identified in medullary neuronal pools involved a cardiovascular regulation. It is hypothesized that these opioid peptides serve as neuromodulators in the neural circuits mediating cardiovascular reflexes. Our preliminary studies have shown that these opioid peptides elicits pressor as well as depressor responses depending on the medullary neuronal pool in which they are microinjected. However, their net effect is inhibition of reflex responses to chemoreceptor, baroreceptor, and cardiopulmonary receptor activation. This opioid peptidergic may be activated in situations in which attenuation of cardiovascular reflex responses would be desirable. For example, bradycardia is one of the prominent responses to chemoreceptor, baroreceptor, and cardiopulmonary receptor activation in stressful situations bradycardia may be detrimental to the individual because adequate cardiac function is required for an efficient perfusion of vital organs such as the brain. This proposal is focused on the role of these novel endogenous opioid peptides in cardiovascular regulation, especially the reflexes affecting this system. This proposal is focused on the role of these novel endogenous opioid peptides in cardiovascular regulation, especially the reflexes affecting this system. A multi-disciplinary approach will be used to investigate the mechanism of action of the afore-mentioned opioid peptides in medullo-spinal cardiovascular regulatory mechanisms. Successful completion of these studies will not only enhance our understanding of the mechanisms by which endogenous opioid peptides modulate cardiovascular function, but will also provide a basis for future studies on the role of these peptides in cardiovascular disease.